Please use this identifier to cite or link to this item: http://hdl.handle.net/1946/23627
Introduction: Coarctation of the aorta (CoA) accounts for 3.8% of all congenital heart disease in Iceland. Despite excellent surgical outcomes, CoA can be a life-long disease with high rates of long-term cardiovascular complications. The underlying genetic basis and pathogenesis of CoA remains largely unknown. The aim of this study was to search for sequence variants that affect the risk of CoA in Iceland.
Methods: The CoA cases were Icelanders (N=132) who received the discharge diagnosis of CoA at Landspitali, The National University Hospital (LUH) in Reykjavik between 1984 and 2015. Detailed phenotypic information on CoA cases was gathered through a centralized electronic database on patient’s records (Saga system) as well as paper records at LUH. To identify sequence variants that associate with CoA risk, genome-wide association analysis (GWAS) was performed using 25.5 million sequence variants identified through whole-genome sequencing of 8,453 Icelanders that were subsequently imputed into a large fraction of Icelanders. The GWAS was performed, with the 132 CoA cases and as controls 339,213 Icelanders without CoA, using logistic regression, adjusting for gender, age and county of origin.
Results: Through the CoA GWAS analysis we identified a rare (0.35%) missense variant c.2161C>T in exon 18 of the MYH6 gene that associates with increased risk of CoA. MYH6 is a large gene that encodes the alpha myosin heavy chain (αMHC), a major component of the sarcomere of cardiac muscle. The c.2161C>T mutation associates with CoA with large effect, an odds ratio of 31.4 (95% confidence interval; 14.08, 69.83) and with high significance, P of 3.3 x 10-17. The c.2161C>T results in a change of arginine to tryptophan at amino acid 721 (p.Arg721Trp) in the converter domain of the αMHC protein. This same mutation has previously been reported to associate with sick sinus syndrome. Of the 132 CoA cases, 24 were carriers of c.2161C>T; no significant phenotypic difference was found between CoA carriers and non-carriers of c.2161C>T. This may in part be explained by the small size of the study. The MYH6 c.2161C>T was not found outside of Iceland.
Conclusions and Discussion: The MYH6 gene has not previously been reported to associate with CoA although other very rare mutations in MYH6 have been linked to both familial hypertrophic cardiomyopathy and familial atrial septal defect. The c.2161C>T mutation explains a large fraction or 19% of CoA cases in Iceland, a figure rarely reported in genetic studies of congenital heart disease. Expression of MYH6 has not been detected in the aorta but it is highly expressed throughout life in the atrium and in the ventricle during embryonic cardiogenesis. The p.Arg721Trp mutation in the converter domain of αMHC is predicted to be damaging and might thus affect the contractile function of αMHC in the heart. It is conceivable that p.Arg721Trp predisposes to CoA by reducing the contraction of the developing heart thus reducing blood flow through the aorta which is in line with the hemodynamic theory, a leading theory of CoA pathogenesis. This hypothesis is compatible with the fact that MYH6 is not expressed in the aorta.